Department of Nephrology, Huashan Hospital and Nephrology Institute, Fudan University, Shanghai, China.
Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.
Clin Sci (Lond). 2022 Jan 14;136(1):103-120. doi: 10.1042/CS20211075.
Inflammatory response and renal fibrosis are the hallmarks of chronic kidney disease (CKD). However, the specific mechanism of aldosterone-induced renal injury in the progress of CKD requires elucidation. Emerging evidence has demonstrated that absent in melanoma 2 (AIM2)-mediated inflammasome activation and endoplasmic reticulum stress (ERS) play a pivotal role in the renal fibrosis. Here, we investigated whether overexpression or deficiency of AIM2 affects ERS and fibrosis in aldosterone-infused renal injury. Interestingly, we found that AIM2 was markedly expressed in the diseased proximal tubules from human and experimental CKD. Mechanically, overactivation of AIM2 aggravated aldosterone-induced ERS and fibrotic changes in vitro while knockdown of AIM2 blunted these effects in vivo and in vitro. By contrast, AIM2 deficiency ameliorated renal structure and function deterioration, decreased proteinuria levels and lowered systolic blood pressure in vivo; silencing of AIM2 blocked inflammasome-mediated signaling pathway, relieved ERS and fibrotic changes in vivo. Furthermore, mineralocorticoid receptor (MR) antagonist eplerenone and ERS inhibitor tauroursodeoxycholic acid (TUDCA) had nephroprotective effects on the basis of AIM2 overactivation in vitro, while they failed to produce a more remarkable renoprotective effect on the treatment of AIM2 silence in vitro. Notably, the combination of TUDCA with AIM2 knockdown significantly reduced proteinuria levels in vivo. Additionally, immunofluorescence assay identified that apoptosis-associated speck-like protein (ASC) recruitment and Gasdermin-D (GSDMD) cleavage respectively occurred in the glomeruli and tubules in vivo. These findings establish a crucial role for AIM2 inflammasome in aldosterone-induced renal injury, which may provide a novel therapeutic target for the pathogenesis of CKD.
炎症反应和肾纤维化是慢性肾脏病（CKD）的标志。然而，醛固酮诱导的 CKD 进展中肾脏损伤的具体机制仍需阐明。新出现的证据表明，缺失黑色素瘤 2（AIM2）介导体细胞焦亡和内质网应激（ERS）在肾纤维化中发挥关键作用。在这里，我们研究了 AIM2 的过表达或缺失是否会影响醛固酮输注引起的肾脏损伤中的 ERS 和纤维化。有趣的是，我们发现 AIM2 在人类和实验性 CKD 的病变近端肾小管中明显表达。在机制上，AIM2 的过度激活加剧了醛固酮诱导的 ERS 和纤维化改变，而 AIM2 的敲低则减弱了体内和体外的这些效应。相反，AIM2 缺乏改善了肾脏结构和功能的恶化，降低了蛋白尿水平和体内的收缩压；沉默 AIM2 阻断了炎性小体介导的信号通路，缓解了体内的 ERS 和纤维化改变。此外，在体外基于 AIM2 过激活的情况下，盐皮质激素受体（MR）拮抗剂依普利酮和 ERS 抑制剂牛磺熊脱氧胆酸（TUDCA）对肾脏具有保护作用，而在体外沉默 AIM2 的治疗中，它们未能产生更显著的肾脏保护作用。值得注意的是，TUDCA 联合 AIM2 敲低可显著降低体内的蛋白尿水平。此外，免疫荧光分析鉴定出体内的 ASC 募集和 GSDMD 切割分别发生在肾小球和肾小管中。这些发现确立了 AIM2 炎性小体在醛固酮诱导的肾脏损伤中的关键作用，这可能为 CKD 的发病机制提供一个新的治疗靶点。
